Kynurenic acid is a metabolically related brain constituent with anticonvulsant and neuroprotective properties (Stone, T. W.; Pharmacol. Rev. 1993, 45, 309-379). The biological activities of various derivatives of the kynurenic acid and their kynurenine precursors have been studied (Camacho. E. et al. J. Med. Chem. 2002, 45, 263-274; Varasi, M. et al. Eur. J. Med. Chem. 1996, 31, 11-21; Salituro, F. G. et al. J. Med. Chem. 1994, 37, 334-336). Kynurenine compounds are converted to kynurenic acids in vivo.
An enantioselective synthesis described by Salituro et al. was used for the synthesis of gram quantities of L-4-chlorokynurenine (Salituro, F. G. et al. J. Med. Chem. 1994, 37, 334-336). This synthesis was not practical for scale up on a larger manufacturing scale due to the use of reagents such as trimethyl tin chloride, sodium hydride and tert-buthyllithium and the lack of availability of certain building blocks.
A racemic synthesis of 4-chlorokynurenine was reported in Varasai et al. Eur. J. Med. Chem. 1996, 31, 11-21. However, experiments for the separation of the enantiomers by crystallization of diasteromeric salts were not successful, nor was preparative HPLC substantially successful, due to low solubility.
There is a need for a convenient synthesis for chiral kynurenines and related compounds using commercially available reagents that does not require the use of toxic or highly reactive reagents or extensive purification techniques. There is a need for syntheses suitable for large-scale manufacture and that can produce chiral kynurenines and related compounds in high chemical purity and high chiral purity.
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